1. Technical Field
The invention relates to octahydro-pyrrolo[3,4-b]pyrrole N-oxides, compositions comprising such compounds, methods for making the compounds, salts, and polymorphs, and methods of using said compounds as prodrugs for treating conditions and disorders where modulation of histamine-3 (H3) receptor activity is of therapeutic benefit.
2. Description of Related Technology
Histamine is a well-known modulator of neuronal activity. At least four types of histamine receptors have been reported in the literature, typically referred to as histamine-1, histamine-2, histamine-3, and histamine-4. The class of histamine receptor known as the histamine-3 receptor (also sometimes called the histamine H3 receptor or the H3 receptor) is believed to play a role in neurotransmission in the central nervous system.
The histamine-3 (H3) receptor was first pharmacologically characterized on histaminergic nerve terminals (Arrang et al, “Auto-inhibition of Brain Histamine Release Mediated by a Novel Class (H3) of Histamine Receptor”, Nature, Vol. 302, pp. 832-837 (1983)). The histamine-3 receptor is able to regulate the release of neurotransmitters in the central nervous system and peripheral nervous system, and also in peripheral organs such as the gastrointestinal tract. Histamine-3 ligands have been shown to be able to modulate the release of histamine, dopamine, serotonin, acetylcholine, and other neurotransmitters. The existence of histamine-3 receptors and their established role in modulating neurotransmitter release activity in animal models of disease indicate the utility of histamine-3 ligands for the treatment of disease. This has motivated a search for, and the development of, selective histamine-3 receptor agonists and antagonists (Leurs et al., Nature Reviews Drug Discovery, Vol. 4, pp. 107-120 (2005); Arrang et al. “Highly potent and selective ligands for histamine H3-receptors,” Nature, Vol. 327, pp. 117-123 (1987); Leurs and Timmerman, ed. “The History of H3 Receptor: A Target for New Drugs,” Elsevier (1998)).
The activity of histamine-3 receptors can be modified or regulated by the administration of histamine-3 receptor ligands. The ligands can demonstrate antagonist, inverse agonist, or partial agonist activity. Histamine-3 receptors have been linked to conditions and disorders related to the central nervous system involving memory, cognition, attention, and other neurological processes, wakefulness, obesity, and also peripheral and systemic activities, such as those involved in asthma and allergic rhinitis. Although various classes of compounds demonstrating histamine-3 receptor-modulating activity exist, it would be beneficial to provide additional compounds that can be incorporated into pharmaceutical compositions useful for therapeutic methods.
Prodrugs are a suitable manner for providing therapeutic compounds. Approximately 5-7% of all commercial drugs worldwide are prodrugs (Stella, Expert Opinion on Therapeutic Patents, Vol. 14, pp. 277-280 (2004)). Prodrugs distinguish themselves in one or more significant ways. They are structurally different from the active daughter compound, and they may have distinct physicochemical properties. Prodrugs can therefore be used, for example, to solve drug delivery problems, and in general to overcome some barriers to the utility of the parent drug molecule, for example, they can help bypassing of drug efflux mechanisms, extend and delay drug absorption to extend the period of drug action, and generally improve bioavailability and biodistribution.
The invention relates to octahydro-pyrrolo[3,4-b]pyrrole N-oxides as prodrugs of histamine-3 receptor ligands. As such, the prodrugs of the invention can be useful to treat disorders where modulation of histamine-3 receptor activity is of therapeutic benefit.